We have combined neuropharmacological and neuroimaging techniques to investigate the mechanism of action of antipsychotics and the pathophysiology of schizophrenia. Traditional investigations of the mechanism of action of antipsychotic drugs have focused on neurochemistry. In recent years, neuroimaging studies have demonstrated the importance of regional brain function in understanding schizophrenia. There have been surprisingly few systematic, controlled investigations into the effects of antipsychotic treatment on regional brain function in man. Over the past year, we have succeeded in demonstrating that the atypical neuroleptic, clozapine, is markedly different from typical neuroleptics in its effects on regional brain glucose metabolism in patients with schizophrenia (using PET-FDG). Furthermore, it appears that clozapine's antipsychotic effects may not be due to changes in any single brain region, but on its effects on a network of interacting cortical and subcortical structures. We have also initiated studies using SPECT and the D2 receptor ligand, IBZM, to examine the specific role of D2 blockade in typical and atypical neuroleptic mechanism of action. Finally, because of the limitations of radioactive tracer techniques (i.e., dosimetry and limited anatomic and temporal resolution), we have begun to use fast MRI to study regional brain function (blood flow and deoxyhemoglobin content). A pilot study has been initiated to compare the effects of D2 receptor challenge on regional deoxyhemoglobin content during acute and chronic neuroleptic treatment, attempting to visualize the metabolic effects of depolarization blockade.